The activin A receptor type-1 (ACVR1) gene encodes a kinase that is a member of the bone morphogenetic protein (BMP) type I receptors included in the TGF-β receptor subfamily. Activins signal through a heteromeric complex of receptor serine kinases that include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are transmembrane proteins composed of a ligand-binding extracellular domain having a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I and II receptors form a stable complex after ligand binding. Type II receptors phosphorylate and activate type I receptors, which autophosphorylate and then bind and activate SMAD transcriptional regulators.
Mutations in ACVR1 have been identified in fibrodysplasia ossificans progressiva (FOP) that aberrantly activate ACVR1. FOP is a rare genetic disorder of progressive extraskeletal ossification, leading to profoundly decreased mobility of affected individuals. Patients with classic FOP generally have congenital malformation of the great toes and develop progressive heterotopic ossification within soft connective tissues in characteristic anatomic patterns. A gene mutation for patients with the classic FOP clinical phenotype was mapped to chromosome 2q23-24, and mutations were identified in ACVR1.
Activating mutations in ACVR1 have also been identified in diffuse intrapontine gliomas (DIPGs), which are highly aggressive glial neoplasms of the ventral pons that are difficult to treat, generally in the pediatric population. Surgical resection is unsuitable due to the location at the base of the brain and no chemotherapeutic or target agent has been identified as providing substantial survival benefit; radiotherapy is the standard of care and provides palliative benefit.
Thus, there is a need for further therapies that target ACVR1, including mutated forms of ACVR1.